骨质疏松及肥胖相关表型的遗传变异研究
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摘要
女性较男性更容易发生应力性及骨质疏松性骨折,骨大小(BS)是骨质疏松性骨折的一个重要的风险因子。为研究影响BS变异的性别特异性数量性状位点(QTL),本研究分别对男性和女性BS作了全基因组连锁分析。我们采用双能X射线吸收仪测量了三个骨骼部位的BS,它们分别为:腰椎、髋部和前臂。我们用410个微卫星标记对来自451个家系共3,899个白人(包括1665个男性,2234个女性)样本进行了基因分型。鉴于不同骨骼部位的BS高度相关,我们对三个骨骼部位的BS采用主成分分析得到一个主成分,然后采用这个主成分作为BS的新“复合表型”进行了全基因组连锁分析。分析结果表明,在女性样本中,8号染色体164 cM处(8q24)出现了一个很强的连锁信号,该位点可能是影响BS复合表型的女性特异性QTL(LOD=3.03),但在男性样本中的相应染色体区域没有检测到连锁信号(LOD=0.02,基因一性别相互作用p值=0.046)。另外,我们发现5号染色体130cM(5q23)与男性BS复合表型连锁(LOD=2.97),但在女性样本中的相应染色体区域没有检测到连锁信号(LOD:0.00,基因-性别相互作用p值=0.022)。本研究表明8q24和5q23是影响BS复合表型的性别差异的染色体区域,而这些区域可能包含引起骨大小和骨质疏松性骨折发生率的性别差异的多效基因。同时证明了在寻找与BS相关的基因时考虑性别与基因的相互作用的重要性。
体重指数(BMI)是被广泛用于预测肥胖及其相关疾病发病率和死亡率和进行肥胖遗传学研究的重要指数,而身高是反应骨骼生长和发育的重要生理指标。流行病学、遗传学和细胞分子研究都表明骨骼生长和脂肪产生密切相关。为鉴定引起身高和BMI变异的共同遗传因子,本研究在597个不相关的中国人中采用Affymetix 500K芯片扫描了500,000 SNPs,运用双变量全基因组关联分析寻找影响BMI和身高共变异的基因。我们发现两个SNPs,rsll150978,位于基因ZNF236(锌指蛋白236)上游10kb区域和rs17077512,位于基因FRK(fyn相关激酶)上游15kb区域,与双变量BMI-身高关联,双变量关联p值分别为6.26×10~(-6)和5.88×10~(-6)。基因型为rsll150978 GG纯合子的个体比基因型为AA的纯合子具有较高身高(2.6 cm)和较小BMI身高(1.2kg/m~2),而基因型为GA的杂合子比基因型为GG纯合子具有较高的BMI(2.1 kg/m~2),可能是由于杂合子优势。基因型为rs17077512 AA纯合子的个体比基因型为AC的杂合子具有较高身高(1.5 cm)和BMI(2kg/m~2)。ZNF236是一个新发现的基因,在骨骼发育和肥胖中的功能还不清楚,但是,ZNF236属于锌指蛋白家族成员,锌指蛋白在骨骼发育和肥胖的许多过程中都发挥重要的作用。FRK参与细胞有丝分裂过程,具有抑制生长的功能。同时它在胰岛β细胞增值和凋亡和肥胖相关的糖尿病中具有重要作用。本研究的结果表明,FRK和ZNF236可能是影响人类身高和BMI共变异的两个新基因。
Stress and osteoporotic fractures are much more common in females than males. Bone size (BS) is an important risk factor for osteoporotic fractures. To explore sex-specific quantitative trait loci (QTL) influencing BS variation, we performed genomewide linkage analyses of BS in males and females separately. BS at three skeletal sites (spine, total hip and forearm) was measured using dual-energy X-ray absorptiometry (DXA) scanners. Since BS at different skeletal sites is highly correlated, we extracted a principal component based on BS measurements at the three skeletal sites and used it as new "composite phenotype" of BS for linkage analyses. A total of 3,899 Caucasians (including 1736 male and 2520 female subjects) from 451 pedigrees were genotyped with 410 microsatellite markers. We detected a QTL influencing the composite phenotype of BS in the females (logarithm of odds [LOD] = 3.03) on chromosome 8 at 164 cM but not in the males (LOD = 0.02, P for gene-by-sex interaction = 0.046). In addition, linkage to the composite phenotype of BS was detected in the males on chromosomes 5 at 130cM (LOD = 2.97) but not in the females (LOD = 0.00, P for gene-by-sex interaction = 0.022). Our study identified chromosomal regions that may contain QTLs contributing to sex dimorphism of BS and possibly the differential incidences of osteoporotic fracture in the two genders. It also demonstrated the importance of considering gene-by-sex interaction in the search for BS related genes.
Both body mass index (BMI) is commonly used to predict morbidity and morality from obesity-related diseases and disclose genetic variants that increase an individual's risk for obesity and its complications. Adult human height is an important physical index to reflect skeletal growth and development. Converging evidences from epidemiology, genetics, and cell molecular studies suggest that skeletal growth and obesity are closely related. To identify the common genetic factors shared between BMI and height, we performed the first bivariate genomewide association study in search for genes underlying co-variation of BMI and height, scanning～500,000 SNPs in 597 unrelated homogeneous Chinese. We identified two SNPs rs11150978, 10kb upstream of ZNF236 (zinc finger protein 236) gene and rs17077512, 15kb upstream of FRK(fyn-related kinase) gene, which were bivariately associated with both BMI-height, achieved bivariate association p values of 6.26×10~(-6) and 5.88×10~(-6) , respectively. The subjects of homozygous rs11150978 GG have lower BMI (1.2 kg/m~2) and higher height (2.6 cm) than those of homozygous AA, however, the subjects of the heterozygous GA have higher BMI (2.1 kg/m~2) than those of homozygous GG. The subjects of homozygous rs17077512 AA have higher BMI (2 kg/m~2) and higher height (1.5 cm) than those of heterozygous AC. ZNF236 was a newly identified genes with no known functions on skeletal growth and obesity. However the zinc finger protein families, to which the gene belongs, play very important roles in a variety of processes associated with skeletal growth and obesity. FRK gene functions during G1 and S phase of the cell cycle and suppress growth. It also plays a role in theβ-cell proliferation and death and obesity linked type 2 diabetes. Together with our findings, these evidences support that FRK and ZNF236 may be two novel genes underlying co-variation of human stature and BMI in Chinese.
体重指数(BMI)是被广泛用于预测肥胖及其相关疾病发病率和死亡率和进行肥胖遗传学研究的重要指数,而身高是反应骨骼生长和发育的重要生理指标。流行病学、遗传学和细胞分子研究都表明骨骼生长和脂肪产生密切相关。为鉴定引起身高和BMI变异的共同遗传因子,本研究在597个不相关的中国人中采用Affymetix 500K芯片扫描了500,000 SNPs,运用双变量全基因组关联分析寻找影响BMI和身高共变异的基因。我们发现两个SNPs,rsll150978,位于基因ZNF236(锌指蛋白236)上游10kb区域和rs17077512,位于基因FRK(fyn相关激酶)上游15kb区域,与双变量BMI-身高关联,双变量关联p值分别为6.26×10~(-6)和5.88×10~(-6)。基因型为rsll150978 GG纯合子的个体比基因型为AA的纯合子具有较高身高(2.6 cm)和较小BMI身高(1.2kg/m~2),而基因型为GA的杂合子比基因型为GG纯合子具有较高的BMI(2.1 kg/m~2),可能是由于杂合子优势。基因型为rs17077512 AA纯合子的个体比基因型为AC的杂合子具有较高身高(1.5 cm)和BMI(2kg/m~2)。ZNF236是一个新发现的基因,在骨骼发育和肥胖中的功能还不清楚,但是,ZNF236属于锌指蛋白家族成员,锌指蛋白在骨骼发育和肥胖的许多过程中都发挥重要的作用。FRK参与细胞有丝分裂过程,具有抑制生长的功能。同时它在胰岛β细胞增值和凋亡和肥胖相关的糖尿病中具有重要作用。本研究的结果表明,FRK和ZNF236可能是影响人类身高和BMI共变异的两个新基因。
Stress and osteoporotic fractures are much more common in females than males. Bone size (BS) is an important risk factor for osteoporotic fractures. To explore sex-specific quantitative trait loci (QTL) influencing BS variation, we performed genomewide linkage analyses of BS in males and females separately. BS at three skeletal sites (spine, total hip and forearm) was measured using dual-energy X-ray absorptiometry (DXA) scanners. Since BS at different skeletal sites is highly correlated, we extracted a principal component based on BS measurements at the three skeletal sites and used it as new "composite phenotype" of BS for linkage analyses. A total of 3,899 Caucasians (including 1736 male and 2520 female subjects) from 451 pedigrees were genotyped with 410 microsatellite markers. We detected a QTL influencing the composite phenotype of BS in the females (logarithm of odds [LOD] = 3.03) on chromosome 8 at 164 cM but not in the males (LOD = 0.02, P for gene-by-sex interaction = 0.046). In addition, linkage to the composite phenotype of BS was detected in the males on chromosomes 5 at 130cM (LOD = 2.97) but not in the females (LOD = 0.00, P for gene-by-sex interaction = 0.022). Our study identified chromosomal regions that may contain QTLs contributing to sex dimorphism of BS and possibly the differential incidences of osteoporotic fracture in the two genders. It also demonstrated the importance of considering gene-by-sex interaction in the search for BS related genes.
Both body mass index (BMI) is commonly used to predict morbidity and morality from obesity-related diseases and disclose genetic variants that increase an individual's risk for obesity and its complications. Adult human height is an important physical index to reflect skeletal growth and development. Converging evidences from epidemiology, genetics, and cell molecular studies suggest that skeletal growth and obesity are closely related. To identify the common genetic factors shared between BMI and height, we performed the first bivariate genomewide association study in search for genes underlying co-variation of BMI and height, scanning～500,000 SNPs in 597 unrelated homogeneous Chinese. We identified two SNPs rs11150978, 10kb upstream of ZNF236 (zinc finger protein 236) gene and rs17077512, 15kb upstream of FRK(fyn-related kinase) gene, which were bivariately associated with both BMI-height, achieved bivariate association p values of 6.26×10~(-6) and 5.88×10~(-6) , respectively. The subjects of homozygous rs11150978 GG have lower BMI (1.2 kg/m~2) and higher height (2.6 cm) than those of homozygous AA, however, the subjects of the heterozygous GA have higher BMI (2.1 kg/m~2) than those of homozygous GG. The subjects of homozygous rs17077512 AA have higher BMI (2 kg/m~2) and higher height (1.5 cm) than those of heterozygous AC. ZNF236 was a newly identified genes with no known functions on skeletal growth and obesity. However the zinc finger protein families, to which the gene belongs, play very important roles in a variety of processes associated with skeletal growth and obesity. FRK gene functions during G1 and S phase of the cell cycle and suppress growth. It also plays a role in theβ-cell proliferation and death and obesity linked type 2 diabetes. Together with our findings, these evidences support that FRK and ZNF236 may be two novel genes underlying co-variation of human stature and BMI in Chinese.
引文
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